1. Field of the Invention
This invention relates to pharmaceutical compositions containing polyoxoanions, methods of using them to treat retroviruses in a mammal, and to certain novel polyoxoanions.
2. Background Information
Antimony/tungsten heteropolyanion (HPA) compounds of the formula: EQU (NaSb.sub.9 W.sub.21 O.sub.86).sup.18-
pharmaceutical compositions thereof are described in EP 185584 wherein the alkali and/or alkaline earth and/or ammonium salt of the heteropolyanion are disclosed as being useful in the treatment of AIDS and similar syndromes. The mixed ammonium/sodium salts of the heteropolyanion of the formula set forth above, are generally referred to as HPA 23. FR 2245374 and FR 23343 disclose HPA 23 as being useful in treating viral infections responsible for sarcoma, leukemia, encephalomyocarditis and vesicular stomatitis.
BE 848836 describes the synergistic pharmaceutical combination of HPA23 or salts thereof and interferon as effective against leukemia and sarcoma viruses.
FR 2424028 discloses tungsten/arsenic heteropolyanions of the formula (1): EQU [As.sub.4 W.sub.40 O.sub.140 ].sup.-28 (I)
and the salts thereof having the formula (II): EQU [M.sup.+x (As.sup.+3).sub.4 (W.sup.+6).sub.40 (O.sup.-2).sub.140 ].sup.-(28-x) B.sub.1.sup.+(28-x) (II)
wherein:
M.gtoreq.1 alkaline earth, transition (especially the first series) of Group IIIA, IVA, VA metal; the total charge, X, on M is &gt;27; PA1 B.sub.1 is a monovalent alkali metal such as Na, K, Ba, Ag, Cu, Zn, Mn, Fe, Co or Ni. PA1 M is either absent or it represents an alkali or alkaline earth metal, other than sodium; PA1 n is 19 when M is absent or n is 19--p, where p is the charge on the ion M; PA1 X represents an element that becomes a cation, such as B, Al, Ga, In, Y, La, Ce, Pr, Nd, Sm, Eu, Gd, Ho, and Yb: PA1 M is tungsten or molybdenum: PA1 O is oxygen; PA1 H is hydrogen: PA1 x and p are positive integers with x being any of 1, 2, 6, 12 and 18. PA1 1. K.sub.6 [BVW.sub.11 O.sub.40 ] PA1 2. 1,2-K.sub.5 [PV.sub.2 W.sub.10 O.sub.40 ] PA1 3. K.sub.7 [BV.sup.IV W.sub.11 O.sub.40 ] PA1 4. .beta.-Cs.sub.5 [PV.sub.2 W.sub.10 O.sub.40 ] PA1 5. K.sub.6 [SiTiW.sub.11 O.sub.40 ] PA1 6. K.sub.7 [PTi.sub.2 W.sub.10 O.sub.40 ] PA1 7. Na.sub.12 [P.sub.2 W.sub.15 O.sub.62 ] PA1 8. K.sub.9 (NH.sub.4)H.sub.2 [(OCe).sub.3 (PW.sub.9 O.sub.34).sub.2 ]
The compounds of formula (II) are disclosed as having anti-viral activity and as being useful in human and veterinary medicine for controlling herpes, leukemia and sarcoma viruses.
BE 861233 discloses tungsten/antimony heteropolyanion compounds of the formula: EQU [MSb.sub.9 W.sub.21 O.sub.86 ].sup.-n
wherein:
which are useful for the treatment of leukemia and sarcoma viruses.
Japanese Patent 62 [1987]-230619 discloses alkalisalts of heteropolyacid ions, active against friend leukemia viruses, having the formula: EQU [XM.sub.12 O.sub.40 H.sub.x ].sup.-p
wherein:
Unlike the active compounds of the present invention, HPA 23. the most often cited heteropolyanion, has a total anion charge of -18, whereas the compounds active in the compositions disclosed herein each have a total anion charge of about -5 to -12, and preferably a total charge of about -5 to -7 per unit of dodecametalate framework.
Traditionally, as shown in the art, in order to change the overall charge of heteropolyanions, the central heteroatom has been changed. In the chemical compositions disclosed herein, the surface negative charge is increased by replacing tungsten cations with lower oxidation state metals such as vanadium (V(+4 or +5)) or titanium (Ti(+4)).
Many of the heteropolyanions known in the art are associated with serious side effects such as granulocytopenia and nephrotoxicity. In addition, very few of the known compounds are active against HIV or other retroviruses. Currently, only one drug Retrovir (AZT) is approved for treatment of HIV/AIDS. AZT is not a cure and in addition to serious side effects must be administered 4-6 times a day, and is very expensive. Given the worldwide scientific focus on AIDS and related syndromes, and the task of finding compounds useful in the treatment of these disease states as well as other retroviral diseases, there is a need for compounds with lower toxicity which are active against retroviruses, and particularly against HIV, and which can be dosed on a less frequent schedule.